Abstract Proper regulation of the PI-3 kinase (PI3K) pathway is critical for normal development, activation and homeostasis in many tissues, including in mast cells. Several negative regulators of the PI3K pathway have been extensively characterized, two of which are known tumor suppressors. Recently, another negative regulator of the PI3K pathway was identified. PIK3IP1 is a transmembrane protein that may act by binding the catalytic protein p110 and preventing its activation. Thus far, very little is known about the possible role of PIK3IP1 in the regulation of leukocyte development or activation. We have found that PIK3IP1 is expressed in mast cells. Importantly, we have now found that mast cells from PIK3IP1 knockout mice are hyper-sensitive to activation by IgE and antigen, which acts through the receptor FceRI. We will therefore determine the effects of PIK3IP1 on specific signaling pathways downstream of FceRI on mast cells, including the role of specific domains within PIK3IP1 for this activity and how it might be modulated by interaction of PIK3IP1 with potential ligands.